Synergistic modulation of FLT3 kinase using a FLT3 inhibitor and a farnesyl transferase inhibitor

Abstract

The invention is directed to a method of inhibiting FLT3 tyrosine kinase activity or expression or reducing FLT3 kinase activity or expression in a cell or a subject comprising the administration of a farnesyl transferase inhibitor and a FLT3 kinase inhibitor selected from compounds of Formula I′: Included within the present invention is both prophylactic and therapeutic methods for treating a subject at risk of (or susceptible to) developing a cell proliferative disorder or a disorder related to FLT3.

What is claimed is: 
     
       1. A method of treating a disorder selected from the group consisting of acute myeloid leukemia, acute lymphocytic leukemia and myelodysplastic syndrome comprising administering to a subject in need thereof a therapeutically effective amount of (1) a FLT3 kinase inhibitor that is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof and (2) a farnesyl transferase inhibitor that is (+)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone, or a pharmaceutically acceptable acid addition salt thereof. 
     
     
       2. The method of  claim 1  further comprising administering to the subject a therapeutically effective amount of chemotherapy. 
     
     
       3. The method of  claim 1  further comprising administering to the subject a therapeutically effective amount of radiation therapy. 
     
     
       4. The method of  claim 1  further comprising administering to the subject a therapeutically effective amount of gene therapy. 
     
     
       5. The method of  claim 1  further comprising administering to the subject a therapeutically effective amount of immunotherapy. 
     
     
       6. A method of treating a disorder selected from the group consisting of acute myeloid leukemia, acute lymphocytic leukemia and myelodysplastic syndrome comprising administering to a subject in need thereof a therapeutically effective amount of (1) a first pharmaceutical composition comprising a FLT3 kinase inhibitor that is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, and (2) a second pharmaceutical composition comprising a farnesyl transferase inhibitor that is (+)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-1-methyl-2(1H)-quinolinone, or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier. 
     
     
       7. The method of  claim 6  further comprising administering to the subject a prophylactically effective amount of chemotherapy. 
     
     
       8. The method of  claim 6  further comprising administering to the subject a prophylactically effective amount of radiation therapy. 
     
     
       9. The method of  claim 6  further comprising administering to the subject a prophylactically effective amount of gene therapy. 
     
     
       10. The method of  claim 6  further comprising administering to the subject a prophylactically effective amount of immunotherapy. 
     
     
       11. A method of treating a disorder selected from the group consisting of acute myeloid leukemia, acute lymphocytic leukemia and myelodysplastic syndrome comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical composition comprising a FLT3 kinase inhibitor that is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof, a farnesyl transferase inhibitor that is (+)-6-[amino(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]-4-(3-chlorophenyl)- 1 -methyl-2(1H)-quinolinone or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier. 
     
     
       12. The method of  claim 11  further comprising administering to the subject a therapeutically effective amount of chemotherapy. 
     
     
       13. The method of  claim 11  further comprising administering to the subject a therapeutically effective amount of radiation therapy. 
     
     
       14. The method of  claim 11  further comprising administering to the subject a therapeutically effective amount of gene therapy. 
     
     
       15. The method of  claim 11  further comprising administering to the subject a therapeutically effective amount of immunotherapy.